rs71453291

Variant names:

• chr12-52469144-C-G
• rs71453291
• NM_173086.5:c.1613G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-52469144-C-G
• chr12-52469144-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173086.5(KRT6C):​c.1613G>C​(p.Gly538Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,614,032 control chromosomes in the GnomAD database, including 781 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (35 hom., cov: 32)
  • Exomes 𝑓: 0.029 (746 hom.)
• Consequence: KRT6C NM_173086.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.82
• Publications: 9 publications found

Genes affected

KRT6C (HGNC:20406): (keratin 6C) Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins. The type II keratins are clustered in a region of chromosome 12q13. [provided by RefSeq, Jul 2009]

KRT6C Gene-Disease associations (from GenCC):

• palmoplantar keratoderma, nonepidermolytic, focal or diffuse

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037206411).
• BP6: Variant 12-52469144-C-G is Benign according to our data. Variant chr12-52469144-C-G is described in ClinVar as Benign. ClinVar VariationId is 1600014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0191 (2915/152316) while in subpopulation NFE AF = 0.0306 (2083/68016). AF 95% confidence interval is 0.0295. There are 35 homozygotes in GnomAd4. There are 1307 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2915 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173086.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT6C	NM_173086.5	MANE Select	c.1613G>C	p.Gly538Ala	missense	Exon 9 of 9	NP_775109.2	P48668

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRT6C	ENST00000252250.7	TSL:1 MANE Select	c.1613G>C	p.Gly538Ala	missense	Exon 9 of 9	ENSP00000252250.6	P48668

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2914 AN: 152198 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0162

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0306

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.0204 AC: 5128 AN: 251350 AF XY: 0.0207

Gnomad AFR exome AF: 0.00535

Gnomad AMR exome AF: 0.0144

Gnomad ASJ exome AF: 0.0306

Gnomad EAS exome AF: 0.000598

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.0305

Gnomad OTH exome AF: 0.0228

GnomAD4 exome AF: 0.0293 AC: 42764 AN: 1461716 Hom.: 746 Cov.: 36 AF XY: 0.0287 AC XY: 20903 AN XY: 727172

African (AFR) AF: 0.00571 AC: 191 AN: 33470

American (AMR) AF: 0.0146 AC: 652 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0324 AC: 846 AN: 26132

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39700

South Asian (SAS) AF: 0.00999 AC: 862 AN: 86248

European-Finnish (FIN) AF: 0.0150 AC: 803 AN: 53420

Middle Eastern (MID) AF: 0.0168 AC: 97 AN: 5762

European-Non Finnish (NFE) AF: 0.0340 AC: 37793 AN: 1111890

Other (OTH) AF: 0.0250 AC: 1511 AN: 60378

GnomAD4 genome AF: 0.0191 AC: 2915 AN: 152316 Hom.: 35 Cov.: 32 AF XY: 0.0175 AC XY: 1307 AN XY: 74482

African (AFR) AF: 0.00558 AC: 232 AN: 41562

American (AMR) AF: 0.0161 AC: 247 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 109 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4826

European-Finnish (FIN) AF: 0.0135 AC: 144 AN: 10628

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0306 AC: 2083 AN: 68016

Other (OTH) AF: 0.0246 AC: 52 AN: 2112

Alfa AF: 0.0289 Hom.: 31

Bravo AF: 0.0195

TwinsUK AF: 0.0359 AC: 133

ALSPAC AF: 0.0304 AC: 117

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0348 AC: 299

ExAC AF: 0.0195 AC: 2365

EpiCase AF: 0.0311

EpiControl AF: 0.0293

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.8
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.34
Sift	Benign	0.28	T
Sift4G	Uncertain	0.035	D
Polyphen		0.54	P
Vest4		0.085
MPC		0.18
ClinPred		0.019	T
GERP RS		2.6
Varity_R		0.11
gMVP		0.59
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71453291; hg19: chr12-52862928; COSMIC: COSV107254427;